Serine/threonine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10517878-B2
Application number	US-201916286955-A
Country	US
Kind code	B2
Filing date	Feb 27, 2019
Priority date	Dec 6, 2013
Publication date	Dec 31, 2019
Grant date	Dec 31, 2019

Abstract

Compounds having the formula I wherein R 1 , X 1 , X 2 , X 3 and X 4 as defined herein are inhibitors of ERK kinase. Also disclosed are compositions and methods for treating hyperproliferative disorders.

First claim

We claim:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof;
wherein
X 1 is N or CH;
X 2 is O;
X 3 is C(R 4 ) 2 ;
X 4 is CR 2 R 3 ;
R 1 is (i) a 4 to 7 membered saturated or partially unsaturated heterocyclyl containing an oxygen atom; or, (ii) a heteroaryl selected from the group consisting of 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-3-yl, 2-ethyl-2H-pyrazol-3-yl, 2-methyl-2H-pyrazol-3-yl, 2-isopropyl-2H-pyrazol-3-yl, 1-methyl-1H-pyrazol-5-yl, 1-ethyl-1H-pyrazol-5-yl, 4-methylthiazol-2-yl, 1-methyl-1H-[1,2,4]triazol-3-yl, 2-methyl-2H-[1,2,3]-triazol-4-yl, 1-methyl-1H-[1,2,4]-triazol-5-yl, 1,3-dimethyl-1H-pyrazol-4-yl, 1,3,5-trimethyl-1H-pyrazol-4-yl, 1-methyl-1H-tetrazol-5-yl, 2-methyl-2H-tetrazol-5-yl, 5-methyl-1,3,4-thiadizol-2-yl, oxetan-3-yl, 3-methyloxetan-3-yl, tetrahydropyran-4-yl, tetrahydro-2H-pyran-4-yl, tetrahydropyran-3-yl, 2-methyl-tetrahydropyran-4-yl, 2,2-dimethyl-tetrahydropyran-4-yl, 2-hydroxymethyltetrahydropyran-4-yl, 3-fluorotetrahydropyran-4-yl and tetrahydrofuran-3-yl;
R 2 is selected from the group consisting of:
(a) C 1-10 alkyl,
(b) C 2-10 alkenyl,
(c) C 1-10 haloalkyl,
(d) C 3-7 cycloalkyl or C 3-7 cycloalkyl-C 1-6 alkyl,
(e) C 3-7 halocycloalkyl or C 3-7 halocycloalkyl-C 1-6 alkyl,
(f) C 1-10 hydroxyalkyl or C 1-10 dihydroxyalkyl,
(g) C 1-3 alkoxy-C 1-6 alkyl,
(h) C 1-3 alkylthio-C 1-6 alkyl,
(i) C 1-10 cyanoalkyl,
(j) phenyl, phenyl-C 1-3 alkyl, phenoxy or benzyloxy-C 1-3 alkyl,
(k) heteroaryl, heteroaryl-C 1-3 alkyl or heteroaryloxy wherein said heteroaryl moiety is selected from the group consisting of pyrazolyl, imidiazolyl, oxazolyl, isoazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrid-2(1H)-one and 1-alkylpyrid-2(1H)-one and each said heteroaryl is independently optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, oxide, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, C 3-6 cycloalkyl and C 1-6 alkyl wherein said C 1-6 alkyl is optionally independently substituted with one or more groups independently selected from halogen, oxo, hydroxyl or C 1-6 alkoxy; and
(l) phenylthio or phenylthio-C 1-6 alkyl; and
R 3 and R 4 are independently hydrogen or C 1-3 alkyl;
wherein any phenyl moiety is optionally substituted one or more halogen, cyano, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkyl wherein said C 1-6 alkyl is optionally independently substituted with one or more groups independently selected from halogen, oxo, hydroxyl or C 1-6 alkoxy; and,
wherein each cycloalkyl is independently and optionally substituted with one to three groups selected from halogen, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy.

2. The compound according to claim 1 selected from:
4-(3-benzyl-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine;
4-(3-benzyl-3-methyl-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine;
4-(3-benzyl-3-methyl-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine;
4-(3-benzyl-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine;
4-(3-(4-chlorobenzyl)-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine;
4-(3-(4-fluorobenzyl)-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine;
4-(3-isobutyl-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine;
4-(3-(3-fluoro-4-methoxybenzyl)-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine;
4-(3-(4-chlorobenzyl)-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine;
4-(3-(3-fluoro-4-methoxybenzyl)-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine;
4-(3-(4-methoxybenzyl)-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine;
N-(1-methyl-1H-pyrazol-5-yl)-4-(3-(2-methylbutyl)-3,4-dihydro-5-oxa-1,2.2a 1 -triazaacenaphthylen-7-yl)pyrimidin-2-amine;
4-(3-(3,4-difluorobenzyl)-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine;
4-(3-(3,4-difluorobenzyl)-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine;
4-(3-(4-fluorobenzyl)-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine;
4-(3-benzyl-4-methyl-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine;
4-(3-(3-methoxybenzyl)-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine;
4-(3-(3-chloro-4-fluorobenzyl)-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine;
4-(3-(3-chloro-4-fluorobenzyl)-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine;
4-(3-(3-chlorobenzyl)-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine;
4-(3-cyclopropyl-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine;
4-(3-(3-chlorobenzyl)-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine;
4-(3-(3-methoxybenzyl)-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine; and
N-(1-methyl-1H-pyrazol-5-yl)-4-(3-propyl-3,4-dihydro-5-oxa-1,2,2a 1 -triazaacenaphthylen-7-yl)pyrimidin-2-amine.

3. The compound of claim 1 wherein R 1 is selected from the group consisting of 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-3-yl, 2-ethyl-2H-pyrazol-3-yl, 2-methyl-2H-pyrazol-3-yl, 2-isopropyl-2H-pyrazol-3-yl, 1-methyl-1H-pyrazol-5-yl, 1-ethyl-1H-pyrazol-5-yl, 1,3-dimethyl-1H-pyrazol-4-yl, and 1,3,5-trimethyl-1H-pyrazol-4-yl.

4. The compound of claim 3 wherein R 1 is 1-methyl-1H-pyrazol-5-yl.

5. The compound of claim 1 wherein R 2 is optionally substituted phenyl-C 1-3 alkyl and R 3 is hydrogen.

6. The compound of claim 1 wherein R 2 is optionally substituted heteroaryl-C 1-3 alkyl and R 3 is hydrogen.

7. The compound of claim 1 wherein R 2 is optionally substituted phenoxy or heteroaryloxy, and R 3 is hydrogen.

8. The compound of claim 1 wherein R 2 is optionally substituted benzyl.

9. The compound of claim 1 wherein R 3 is hydrogen.

10. The compound of claim 1 wherein each R 4 is hydrogen.

11. The compound of claim 1 wherein one of R 4 is methyl.

12. The compound of claim 1 wherein CR 2 R 3 is in the (S) configuration.

13. The compound of claim 1 wherein CR 2 R 3 is in the (R) configuration.

Assignees

• Genentech Inc

Inventors

• Kolesnikov Aleksandr
• Do Steven

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title